Cannabinoids

An analog of arachidonylethanolamide (anandamide) that is a potent, selective CB1 cannabinoid receptor agonist. The methyl group at the C-2 position of arachidonic acid gives the compound enhanced metabolic stability. It can fully substitute for Δ9-THC in animal self-administration tests.

AZ513 is a reversible, noncompetitive FAAH inhibitor. It also binds non-competitively at a site distinct from the catalytic site. AZ513 is 20-fold more potent against rat FAAH (IC50 27 nM) than the human form (IC50 551 nM).

An arachidonic acid derivative that is an endogenous ligand for the CB cannabinoid receptor and for the VR1 vanilloid receptor. Inhibits calcium currents in neuroblastomas and neurons. Activates the MAP kinase signaling pathway. Inhibits proliferation and induces apoptosis of lymphocytes and human breast cancer cells.

CP-945,598 is a potent, selective, high affinity and competitive cannabinoid type 1 (CB1) receptor antagonist. CP-945,598 inhibits both basal and cannabinoid agonist-mediated CB1 receptor signaling in vitro and in vivo. CP-945,598 exhibits anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding.CP-945,598 is also known as 1-(8-(2-Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)-4-(ethylamino)piperidine-4-carboxamide. This orally active antagonist of the cannabinoid CB-1 receptor may be used in the treatment of obesity.

Docosahexaenoyl ethanolamide (DHEA) is a lipid signaling molecule present in brain and retina at concentrations, similar to those for arachidonoyl ethanolamide. DHEA binds to the rat brain CB1 receptor with a Ki of 324 nM. It exhibits anti-inflammatory and organ protective activity. Studies show that docosahexaenoyl ethanolamide is the mediator of neurite growth and synaptogenesis in hippocampal neurons, resulting in enhanced synaptic activity.

Eicosapentaenoyl ethanolamide (EPEA) is a lipid mediator that has been found to suppress lifespan extension resulting from dietary restriction in C. elegans and also to have antiproliferative and anti-inflammatory actions. In C. elegans, it is believed to act as a metabolic signal that couples nutrient availability with growth and lifespan. EPEA is a member of the N-acylethanolamines (NAEs), lipid-derived signaling molecules that include the mammalian endocannabinoid arachidonoyl ethanolamide (AEA). In mammals, NAEs are believed to act primarily through cannabinoid receptors, although they can also interact with a variety of other targets, and EPEA has been shown to act as a CB1 and CB2 receptor agonist. However, C.elegans does not possess clear orthologues of the mammalian cannabinoid receptors which suggests that there are unidentified NAE receptors in nematodes that are possibly conserved mediators of NAE signaling.

GAT211 is a positive allosteric modulator (PAM) of cannabinoid CB1 receptor signaling. GAT211 was found to amplify the therapeutic effect of endocannabinoids without the negative side effects of psychoactivity or tolerance. GAT211 caused a CB1-dependent suppression of paclitaxel-induced mechanical and cold allodynia with no sign of tolerance over 19 days of administration.

GSK575594A is a selective agonist of human GPR55. It is specific for human over rodent GPR55. GSK575594A had no activity across a set of more than 200 validated molecular target assays from diverse classes including kinases, proteases and other enzymes, GPCRs, ion channels, nuclear receptors, and membrane transporters.

GW833972A is a CB2 cannabinoid receptor agonist with 1000-fold selectivity relative to CB1. It is, however, 15-fold less potent than HU210 for CB2 (Ki 7.8 vs. 0.52 nM). The antitumor compound oxaliplatin induces marked hypersensitivity to cold, heat, and chemical pain stimuli (to the point where oxaliplatin therapy has to be discontinued). The hyperalgesia effect is almost completely blocked by pretreatment with GW833972A.GW833972A is a CB2 receptor agonist with 1000-fold selectivity relative to CB1. GW833972A is 15 fold less potent than HU210 for CB2 (Ki 7.8 vs. 0.52 nM). The compound was used to determine the role of CB2 in airway sensory nerve function.

Hemopressin is an endogenous hypotensive nonapeptide derived from hemoglobin. Hemopressin reduces appetite, acting as a cannabinoid CB1 inverse agonist. It blocks signaling by CB(1) receptors but not by other members of family A G protein-coupled receptors (including the closely related CB(2) receptors.

JJKK-048 is a cell penetrant ultrapotent and highly selective inhibitor of monoacylglycerol lipase (MAGL) that exhibits a low cross-reactivity with other endocannabinoid targets. JJKK-048 is an irreversible inhibitor that binds to the active site S122.

JW651 is a potent selective inhibitor of MAGL, the enzyme predominantly responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). JW651 inhibited mouse MAGL with an IC50 ~38 nM compared to 10,380 for ABHD6, a serine hydrolase that acts as an alternative hydrolase of 2-AG and >100,000 for FAAH, the hydrolase that degrades the endocannabinoid anandamide (AEA). JW651 was used as the MAGL inhibitor along with JW912, a fluorescent inihibitor of both MAGL and ABHD6.

JZL184 selectively inhibits MAGL, the enzyme predominantly responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Anandamide and 2-AG are the two endogenous endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Anandamide is predominantly metabolized by fatty acid amide hydrolase (FAAH), whereas monoacylglycerol lipase (MAGL) is thought to be the enzyme primarily responsible for the degradation of 2-AG. It is difficult to separate the activities of the two because most currently available inhibitors of MAGL are not selective, and also inhibit FAAH or other enzymes. JZL 184 is the first selective inhibitor of MAGL with nanomolar portency and over 200-fold selectivity for MAGL vs FAAH. When administered to mice, JZL184 increased levels of 2-arachidonoylglycerol in the brain by about 8-fold, with no effect on levels of anandamide.

KT109 is a potent and selective inhibitor of Diacylglycerol lipase DAGLβ. Diacylglycerol lipases DAGLα and DAGLβ are serine hydrolases that biosynthesize the endocannabinoid 2-arachidonoylglycerol (2-AG). A lack of selective inhibitors has hampered study of these lipases. KT109 is a potent and selective DAGLβ inhibitor with an IC50 of 42 nM, ~60-fold selectivity for DAGLβ over DAGLα, and negligible activity against FAAH, MGLL and ABHD11, other key enzymes involved in endocannabinoid signaling. KT109 shows some inhibitory activity against PLA2G7 (IC50 = 1 μM) but no inhibitory activity against cytosolic phospholipase A2 (cPLA2 or PLA2G4A). The main off target inhibition against ABHD6 (IC50 = 16 nM) can be controlled for by use of the related compound, KT195, a potent (IC50 = 10 nM) and selective ABHD6 inhibitor with negligible activity against DAGLβ. KT109 disrupts the lipid network involved in macrophage inflammatory responses, lowering 2-AG, as well as arachidonic acid and eicosanoids, in mouse peritoneal macrophages.

KT195 is a potent (IC50 = 10 nM) and selective inhibitor of α/β-hydrolase domain-containing 6 (ABHD6), a serine hydrolase that acts as an alternative hydrolase of the endocannabinoid 2-arachidonoylglycerol (2-AG). KT195 has negligible activity against other serine hydrolases such as DAGLβ and has been used as a control probe for studies of DAGLβ as well as being a probe on its own to study ABHD6. KT195 treatment of Neuro2A cells caused significant accumulation of 2-AG. KT195 also lowered interleukin-1β (IL-1β) secretion from lipopolysaccharide-treated macrophages suggesting ABHD6 involvement in this activity as well.

MJN110 is a potent selective inhibitor of MAGL, the enzyme predominantly responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) with >10,000 selectivity over FAAH, the hydrolase that degrades the endocannabinoid anandamide (AEA). MJN110 inhibits rat, mouse and human MAGL with IC50 values ranging from < 100 nM in rat to an IC50 of ~1 nM with 10- and 100-fold selectivity over closely related ABHD6, a serine hydrolase that acts as an alternative hydrolase of 2-AG, and LYPLA1/2 in human PC3 cells. MJN110 showed potent anti-hyperalgesic activity in a rat model of diabetic neuropathy, showing a therapeutic potential for treating diabetes chronic pain.

N-Arachidonylmaleidmide (NAM) is structurally similar to the MAGL substrate 2-AG and displays a high potency for inhibition of MAGL. It is thought that NAM binds MAGL at the substrate binding site and inhibits enzyme activity through the Michael addition reaction at the Cys201, and to a lesser extent Cys242, residue of MAGL. In cerebellar rat membranes, NAM inhibits MAGL-like activity with an IC50 of 140 nM.

NIDA-41020 is a CB1 cannabinoid receptor antagonist. NIDA-41020 is structurally similar to Rimonabant, which is currently in clinical development. NIDA-41020 is less lipophilic; developed at NIDA as a potential radioligand for CB1 receptors, Ki = 4.1 nM [in comparison AM 251, AM 281, SR 141716 (Rimonabant) have Ki of 0.6, 4.5 and 1.8 nM respectively].

PF 3845 is a potent, irreversible inhibitor of fatty acid amide hydrolase (FAAH), the principle enzyme involved in the degradation of the endocannabinoid anandamide. The endocannabinoid system is a target for therapeutic pain relief. PF-3845 is a covalent inhibitor that carbamylates FAAH′s serine nucleophile. It high selectivity over other enzymes including FAAH-2. In mouse studies, PF-3845 has been shown to raise brain anandamide levels for up to 24 hr; and in a rat model it produced significant reduction of inflammatory pain..

PF-04457845 is a potent, orally active, irreversible inhibitor of fatty acid amide hydrolase (FAAH), the principle enzyme involved in the degradation of the endocannabinoid anandamide. PF-04457845 is a covalent inhibitor that carbamylates FAAH′s serine nucleophile. It was shown to be both potent and selective against other serine hydrolases. It has an IC50 value of 7.2 nM for human FAAH. The endocannabinoid system is a target for therapeutic pain relief. In a rat model of inflammatory pain, PF-04457845 produced significant reduction of inflammatory pain with efficacy comparable to that of naproxen at 10 mg/kg.

R(+)-Methanandamide is metabolically stable congener of anandamide that has higher affinity for the cannabinoid receptor. Of the analogs tested, (R)-methanandamide exhibited the highest affinity for the cannabinoid receptor with a Ki of 20 +/- 1.6 nM, 4-fold lower than that of anandamide (Ki = 78 +/- 2 nM). (R)-methanandamide exhibits high stability to aminopeptidase hydrolysis. Experiments with mice have demonstrated that (R)-methanandamide also posseses cannabimimetric properties in vivo, as established by the four tests of hypothermia, hypokinesia, ring immobility, and antinociception.

Rimonabant hydrochloride (SR-141716A) is a potent and selective CB1 cannabinoid inverse agonist/antagonist with a Ki of 1.6 nM, minimal affinity for CB2, and and some GPR55 agonist activity. Rimonabant was developed as an anti-obesity drug because of its appetite suppressant activity, but was taken off the market because of side effects of depression and anxiety.

In mice, WWL70 guards against neuropathic pain stimulated by chronic constriction injury. It decreases the inflammatory response in the ipsilateral spinal cord, dorsal root ganglion (DRG) and sciatic nerve. WWL70 is considered as an anti-inflammatory therapeutic agent, that has the ability to prevent the synthesis of PGE2 (prostaglandin E2) and PGE2-G (PGE2-glyceryl ester).WWL70 is a selective inhibitor of α/β-hydrolase domain-containing 6 (ABHD6), a serine hydrolase that acts as an alternative hydrolase of the endocannabinoid 2-arachidonoylglycerol (2-AG). It has an IC50 value of 55-70 nM and 90-95% inihibition of ABDH6. WWL70 hs been used in a variety of studies as an ABHD6 antagonist. It was shown to rescue impaired function of mGluR5 signaling, resulting in pain inhibition in arthritic rats. WWL70 was also used to show that ABHD6 is involved in brown adipose function and white adipose browning, and is a potential therapeutic target for obesity and type 2 diabetes.

Δ9-Tetrahydrocannabinol or Δ9-THC is a psychoactive ingredient in marijuana that is known to function as a neuroprotective antioxidant21. In vivo microdialysis studies have reported that Δ9-THC can enhance extracellular dopamine efflux in the nucleus accumbens of conscious, freely-moving rats22.Agonist at CB1 and CB2 cannabinoid receptors. Hallucinogen; major psychoactive component of marijuana from Cannabis sativa.